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Our Memories, Our Selves

The radio was on in the background the other day, low volume as usual, when I found myself inclining toward vaguely familiar music. It was something I had once known very well, and as I began to listen more intently, a few swells of melody pushed a button somewhere in my brainpan: Gershwin. The overture to ''Of Thee I Sing.''

I hadn't heard that music in about 30 years, but way back then I heard it a lot, during weeks of rehearsals for the high-school musical. Hearing the overture, I remembered the words of songs I hadn't sung in decades, as well as the one line I was entrusted to utter in the play -- ''Does the President live here all year round?'' I even remembered the mischievous arch in my friend Chuck's eyebrows as he gestured to me to sneak outside for a smoke. I could still point out the tree we hid behind.

I remember.. . .How odd that an active verb lies at the heart of memory. The process is so dependent on unbeckoned cues and serendipitous triggers, so meandering in its journey, that it often feels like a passive, episodic and accidental activity, a cognitive walkabout in the wilderness of one's own past. The song on the radio. Kitchen smells. Afternoon light hitting a beloved landscape, or a loved one's face, just so. For me, the trigger is usually music. When I hear ''Light My Fire,'' I picture a lake in Wisconsin and an unrequited adolescent crush on the resident Elusive Beauty. Bach's Piano Concerto No. 1, and it's a train leaving Venice. Coltrane, sex. And of course ''Teddy Bear Picnic'' takes me all the way back to those waxy yellow 78's spinning round and round on my first record player, in my first room, in the first home I remember.

What makes these memories, like all memories, so remarkable is what lies below the waterline of recollection: molecules at work, molecules darting like small fish inside the brain cells known as neurons, swimming upstream to the nucleus, figuratively nuzzling up to the cell's DNA until the cell shudders with genetic change. Thirty years ago, the exact pattern of a Gershwin tune etched some unique, indelible changes upon a handful of my 70 trillion synapses, the junctions where neurons connect, where electrophysiological impulses leap into a pulsing web of circuitry. Neuroscientists have devoted a great deal of effort to investigating synaptic plasticity -- how these synapses change on the basis of experience. Memory is the residue of those changes.

Around the time I was listening to ''Teddy Bear Picnic,'' the people who studied memory were busy looking for the locus of memory, like Stanley searching for the source of the Nile, a fixed geographic point in the deepest interior of the brain. They studied amnesiacs like the famous patient H.M., who provided several clues to the brain's memory system. Following experimental surgery in 1953, during which the hippocampus and nearby structures were suctioned away, H.M. lost the ability to remember people, places and day-to-day events.

Now, neurobiologists can distinguish numerous kinds of memory at work within one brain, each using different anatomical circuitry. With brain scans, they can follow the retrieval of a memory as it travels, like a scudding cloud, through various precincts of the brain. They can even see synapses change physically on the basis of experience, hinting at a microscopic place where biology and personal history intersect.

Still, our collective ignorance about the mysteries of memory remains huge, surely beyond our capacity to manipulate it, anytime soon, with drugs. Or maybe not. Several new memory-enhancing drugs, designed for Alzheimer's disease but with the potential for broader use, are under consideration by the Food and Drug Administration. And meanwhile, a diverse group of researchers have made spectacular progress on the cellular and genetic front, laying the groundwork for pharmaceutical manipulation of memory.

Three years ago, two biologists at Cold Spring Harbor Laboratory on Long Island, Tim Tully and Jerry Yin, created a fruit fly that exhibits the equivalent of photographic memory. They achieved this feat by prodding the activity of a single gene called CREB, which functions as a kind of master switch that unlocks dozens of other genes. Those liberated genes seem to do the heavy lifting in nerve cells to convert recent experience into long-term memory. ''When I'm grandstanding, I say the CREB switch, and all that it implies for memory enhancers and suppressors, is the e = mc2 of the mind,'' says Tully, a rangy, bearded, boyishly enthusiastic 43-year-old researcher. ''It can be used for great value or for great destruction, and it's up to us to decide how we're going to use it.''

Drugs based on the molecular genetics of memory are probably 10 to 15 years away -- just about the time when aging baby boomers will be grumbling in unison, ''Now where did I put those damn keys?'' Nearly every major pharmaceutical company has a fast-track program for developing memory drugs, and some 200 cognitive enhancers are being actively pursued. The National Institutes of Health is conducting clinical trials of a new class of memory enhancers called Ampakines, and another sort of memory drug, one that might blunt the formation of traumatic memories associated with sexual assaults, may enter clinical trials in California as early as this year.

A future with memory enhancers, according to experts who have begun to wrestle with the issue, means Pandora's got a brand-new box. Will companies someday require employees to use these drugs to improve on-the-job performance? Will society demand that professionals to whom we entrust our safety, like airline pilots and surgeons, use memory enhancers during training? Will students have to submit a urine sample when they turn in their S.A.T.'s? Will parents feel compelled to slip smart drugs into their children's lunch boxes? (Several of the biologists I interviewed for this article have already been asked by friends to recommend or provide drugs that would enhance their children's school performance.) And if victims of traumatic events -- bombings, car accidents, sexual assaults -- are treated with memory-suppressing drugs, will their credibility in legal proceedings be compromised?

Those are just a few of the questions raised by neurobiologists at a meeting last February in London sponsored by the Swiss-based Novartis, one of three pharmaceutical companies that have recently applied to the F.D.A. for approval of a memory-enhancing drug. James L. McGaugh, director of the Center for the Neurobiology of Learning and Memory at the University of California at Irvine, organized the meeting with Steven Rose of Britain's Open University to discuss, as McGaugh put it later, ''what's going to happen if and when somebody hits it big, because it ain't just going to be Alzheimer's patients who are going to want these drugs. And I don't think it's too far away.''

Indeed, Cold Spring Harbor Laboratory has joined Oncogene Sciences and the pharmaceutical giant Hoffmann-La Roche to form Helicon Therapeutics (''the memory company,'' according to a news release) to search for memory-enhancing drugs based on the CREB switch. And Eric R. Kandel, the Columbia University biologist who has pioneered much of the research into the molecular basis of memory, is joining forces with Walter Gilbert, a Harvard University molecular biologist, to form Memory Pharmaceuticals.

What makes the approach of Memory Pharmaceuticals unusual is that Gilbert pays no lip service to the notion of treating serious disorders like Alzheimer's: the company is primarily aiming to make a drug for age-related memory loss, a drug for normal people. Gilbert, a Nobel laureate who helped found Biogen and Myriad Genetics, says that the company has had encouraging results with a compound that treats age-related memory degradation in mice. The compound may be ready for clinical testing in three years, Gilbert says, predicting that it will have ''a massive market, if successful.''

Alzheimer's disease and other age-related dementias tend to be the fig leaf that researchers, biotech entrepreneurs and drug companies hide behind when they talk about ''cognitive enhancers.'' Alzheimer's afflicts nearly four million Americans, and that number may double in 20 years. But there's a much larger market out there, and it's made up of people like me: baby boomers who are still pretty sharp but beginning to wonder about those little memory lapses.

I'm 46, my thinning hair is a moonrise waiting to happen and I just got my first prescription for bifocals, but I still like to think of myself -- against mounting evidence, it would seem -- as youthful and cognitively spry. But when I'm not hearing friends talk about high blood pressure or more acute medical breakdowns these days, I'm hearing that nobody's memory is what it used to be. Just the other night, my wife was reduced to tears by her inability to find some documents. And keys? She has made four sets to leave around the house.

For the most part, such lapses involve short-term memory -- forgetting to take out the garbage, not remembering bits of conversations 10 minutes later, little details that get subsumed in daily business. But I'm also of a generation that tends to flatter itself about its medical sophistication, although it sometimes seems like a kind of me-first hypochondria -- you can't remember someone's name and it's the first sign of Alzheimer's.

There is no question, however, that memory begins to fade with age. The coming wave of memory drugs would not, according to Steven Rose, ''recover the lost memories of one's past. In practice this is not what is even potentially on offer. Rather, we are discussing drugs which may improve the long-term retention and storage of new information, perhaps as trivial and also essential as where one left one's house keys this morning.''

When we talk about memory drugs, we first need to ask, What exactly do we mean by memory? Is it remembering the first time you laid eyes on your lifelong mate, or is it remembering to shut off the stove? Is it remembering to return a call, or is it remembering how to ride a bicycle? Is it remembering the significance of 1492, or is it remembering every delicious second of Bill Mazeroski's circumnavigation of the bases at Forbes Field?

Memory is all those things, and more. Everyone agrees that the key to understanding memory ultimately lies not in molecules but in circuitry. ''Memory is not just one big warehouse, one big storehouse, one tape recorder, however people tend to think of it,'' says Daniel Schacter, a professor at Harvard University and the author of ''Searching for Memory.'' ''It's composed of a number of different, interacting systems and subsystems, and there are a lot of different ways to carve it up.''

A simple definition of memory is much trickier today than it was even a decade ago because of the way scientists have dissected memory into so many parts. There is semantic memory (of factual information) and episodic memory (of past experiences) and priming (unconscious recall of short visual or auditory cues) and ''flashbulb'' memories of defining moments, like J.F.K.'s assassination. There is explicit memory (the memory of what), which relies on the hippocampus, the processing center in the core of the brain, and there is implicit memory (the memory of how), some forms of which reside in the motor cortex and don't seem to need the hippocampus at all. This explains how ''Frederick,'' an Alzheimer's patient studied by Schacter, could remember all the mechanics of playing golf but not how many strokes he made on each hole; sometimes he even forgot where he had hit his ball.

The problems of understanding the circuitry of memory are immense. Humans possess an estimated 1 trillion neurons, plus 70 trillion synaptic connections between them, and it's even more complicated than those numbers suggest. A single neuron may have as many as 10,000 synapses, but during the process of memory formation perhaps only 12 synapses will be strengthened while another 100 will be weakened. The sum of those changes, multiplied neuron by neuron, creates a weighted circuit that amounts to a memory.

The problem of circuitry has been skirted, at least temporarily, by a small and almost willfully iconoclastic group of neuroscientists who have ''gone molecular'' in the most fundamental way. While the majority of neuroscientists study mice or rats or primates, these more reductionist biologists have bet the farm -- their time, their careers, their research money -- on the proposition that simple animals with exceedingly simple brains can reveal some universal biological truths about how memory works.

No one has dominated this area of research more than Eric Kandel, who has been working on the cellular basis of memory for four decades, and no one has more spectacularly demonstrated the potential power of molecular genetics in memory research than Tim Tully and his colleagues at Cold Spring Harbor. The recent industrial competition between these two men extends a lively intellectual rivalry growing out of their shared belief that the CREB switch may be a key to memory.

Because memory is so intensely personal, it is easy to feel offended by the notion that a bunch of molecules with thorny names, identified mostly in animals with no brains to speak of, can presume to explain its intricacies and Proustian richness in humans. That is precisely the bias that Kandel has battled for decades, and he has stuck with it long enough to have something like the last laugh.

When I visited him recently, he ushered me into his bright, uncluttered corner office on the sixth floor of the New York State Psychiatric Institute, part of Columbia's College of Physicians and Surgeons. Both the furnishings and the hospitality had an Old World civility, from a handsome oil portrait to an elegant Mission-style coffee table, laid out with fine china, hot coffee and fresh bagels.

Dressed in a crisp blue-striped shirt and a vibratingly bright bow tie, the 68-year-old Kandel holds forth with witty, erudite and often profane charm. Despite occasional protestations of modesty, he is known among peers for being intellectually territorial and unusually proprietary about his reputation. He's not above remonstrating with colleagues about perceived slights or berating journalists if he doesn't like what they write about him.

The custodial energies expended on his reputation seem largely unnecessary. Many people share the view of Larry Squire, a leading neuroscientist at the University of California at San Diego, who calls Kandel's lifetime devotion to the study of memory a ''monumental'' achievement. Born in Vienna, Kandel fled Nazi-occupied Austria with his family in 1939, attended Erasmus Hall High School in Brooklyn and went to Harvard. There he became interested in psychoanalysis but got fruitfully distracted by neurobiology during medical school. ''I began to think about problems in neurobiology that are relevant to psychiatry,'' he says. ''And I thought: Learning and memory is going to be a tractable problem in my lifetime. You know, not tomorrow, but in 20 or 30 years.''

Kandel began to look for a ''system'' -- science-speak for an animal to study that would tell him something about learning and memory. ''I wanted to take a radically reductionist approach,'' he says. The animal he settled on was a lumpy mollusk called Aplysia californica, a large sea snail that you will never see in a wildlife calendar. It looks like a purplish-green baked potato with ears.

But it was perfect for what Kandel had in mind, which was to see if he could take a simple behavior and detect changes in the inner sanctum of nerve cells as the animal learned. Aplysia obliged handsomely. It has the largest nerve cells in the animal kingdom. It possesses only 20,000 neurons in all (some of them conveniently color-coded by nature, making it easier to sort out the circuitry). And despite its humble looks, Aplysia turns out to have some surprisingly complex behavior. ''One of the wonderful things we began to appreciate is that these goddamn invertebrates can learn anything!'' Kandel says. ''I mean, they can't learn to speak French, but all the things that Pavlov and the behavioral psychologists had talked about -- what we now call implicit, or nondeclarative, forms of memory -- they could do in spades.''

Behavior has always been critical to the scientific study of memory. Whether it's remembering not to touch a hot stove after a single bad experience or how to play the piano after repeated practice, behavior changes with learning. The central conceit of this entire arc of research is that such changes can be measured at the synapses, the gaps between neurons, the points where an electrical impulse traveling through one nerve cell is translated into a squirt of chemicals known as neurotransmitters. These neurotransmitters traverse the tiny synaptic gap and pass the impulse on to the next cell. (To put this activity in proper spatial perspective, consider that a cubic millimeter of cortical tissue -- something that would roughly fit inside this ''o'' -- holds about a billion synapses.) So in order to study the process of memory, you need to find an animal with a behavior that changes, and then literally dissect the cells involved, looking for a biochemical trace of those changes.

Kandel published his first experiment on Aplysia in 1963, and to make a very long and heroic scientific story short, he and his colleagues -- at New York University until 1974, then at Columbia and now financed by the Howard Hughes Medical Institute -- took a simple behavior, the animal's withdrawal of its gill, and deconstructed it in a way that would shame the most industrious literary semiotician. Kandel's team identified the key cells participating in the behavior, worked out the neural circuitry and demonstrated that individual synapses changed when the animal learned to associate an electric shock with a touch -- in crude terms, it would flinch at the slightest touch, a behavior known as sensitization.

The stakes for this whole avenue of inquiry rose considerably during the 1960's and 70's, when a number of scientists made an intriguing observation. If you gave animals a drug that blocked their ability to make new proteins, they suddenly became incapable of forming long-lasting memories. They could learn, but they couldn't convert what they had learned into a permanent memory. The shorthand implications were profound: since genes must be switched on to make new proteins, genes were therefore involved in long-term memory.

In the end, the Columbia researchers took a minimalist route, reducing Aplysia's simple behavior to two nerve cells maintained in a dish, two cells talking to each other in the biochemical language of memory -- or, as Kandel puts it, ''something like memory.'' The group showed that when Cell No. 1 got hit by a neurotransmitter called serotonin, as occurs during sensitization, a chain reaction of molecules was unleashed inside the cell. As a result of the activity of these molecules, which form a signaling system known as the cyclic AMP pathway, Cell No. 1 grew new synaptic connections and therefore communicated more easily with Cell No. 2.

The tongue-twisting names of the constituent molecules in this chain are not important here; what is remarkable is that different molecules in the relay have ultimately been shown to correspond to distinct stages of memory formation in experimental animals. Block one molecule in the relay, and the animal can't learn. Block another, and the animal learns but can't form short-term memory.

The last molecule in this chain played a special role. When researchers followed the molecule's footprints inside the nerve cell, they led right up to the genetic doorstep of memory: a tiny patch of DNA in the nerve cell's nucleus. The molecule was called CREB, which, once it binds to DNA, switches on dozens of other genes. In the spring of 1990, Kandel's group linked CREB to memory. In their two homely neurons, they showed that simply by blocking CREB, none of the events associated with long-term memory -- protein synthesis, growth of synapses and other changes -- occurred. CREB was the gateway to all the changes that lead to a permanent memory. CREB was the gateway to memory's genes.

It is part of Kandel's charm that he sums up this molecular denouement, after more than three decades of work on Aplysia, as ''a very nice beginning.'' In this case, his modesty is well placed. Kandel's group hadn't shown that CREB did anything in an intact animal. That development awaited the ''fly people.''

When I visited Tim Tully recently, there was no fine china and no bagels. In fact, there was no response at all when I knocked on his office door, although I suspected he was inside. Dormitory-strength rock music -- Mott the Hoople, to be specific -- was blaring through the door. When he finally heard me knocking, Tully sheepishly explained that he and his wife had just unearthed some old albums and that he was working through the collection.

Flasks of mutant fruit flies were stacked on the floor of his office in pint bottles that looked like juice containers. A white board on one wall was thick with equations, Tully's attempt to reduce the genetics of memory to the pure language of mathematics.

Unlike Kandel, Tully brings a kind of blue-collar sensibility to his science. He mentions that his mother had wanted him to become a mechanical engineer. ''Somewhere along the line,'' he says, toying with a multichambered plastic gadget on his desk, ''I realized I'd be average among many. But if I had mechanical abilities in biology, I'd stand out! I mean, it's an interesting, rich field for just basic mechanical innovation. And behavior is a great area for it.'' He was a tinkerer; all he needed was a behavior to study.

A self-described redneck who grew up in a small town near Peoria, Ill., Tully received an eye-opening education at the University of Illinois. He studied in the laboratory of the psychologist Jerry Hirsch, which boasted two seemingly disparate research interests: institutional racism and fruit fly genetics. Hirsch acquired a certain notoriety in the 1970's when he joined the scientific attack upon William Shockley and Arthur Jensen, whose theories on the heredity of intelligence argued that blacks were genetically inferior. When Hirsch debated Shockley, Tully prepped him, and he has ever since been sensitive to the social ramifications of genetic research, memory research included.

Tully did postdoctoral research at Princeton and later moved on to Brandeis University. During that time, he finally found a use for his mechanical-engineering talents: he devised a Pavlovian test chamber in which flies could learn a behavior and then be tested for memory retention. The reason Pavlov is a hero to Tully and many others is that his turn-of-the-century experiments with dogs reduced learning and memory to a simple mirror of what happens at the cellular level: the association of two stimuli within a window of time. In Pavlov's case, the dogs associated the sound of a bell with the sight of food and learned to salivate merely at the sound of the bell. A century later, molecular biologists have the tools to look for biochemical salivations in neurons that change when they associate these stimuli. Neurons, Tully believes, are built to reconfigure or retune themselves on the basis of precisely the kind of associative stimuli that Pavlov originally explored.

The ''fly people'' began their modern assault on the puzzle of learning and memory in the 1970's. To the casual observer, fruit flies (Drosophila melanogaster) do not possess conspicuously more cognitive firepower than sea snails. But they do provide a cheap, simple, fast and powerful way to attack the problem, not least because researchers have compiled a virtual encyclopedia of fruit fly genes over decades of study. Hence, a researcher typically needs only to expose flies to radiation or chemicals to create mutations in single genes, then look for oddball cognitive behaviors in the offspring.

In the mid-1970's, the laboratory of Seymour Benzer, a geneticist at the California Institute of Technology, identified a celebrated fly named ''dunce.'' By the late 1970's, it turned out that dunce's problem stemmed from a mutation in a single gene, and that gene involved cyclic AMP -- the same signaling pathway Kandel had identified in his mollusks.

Two different animals, same pathway. That was enough to raise a few eyebrows.

The fly rooms at Cold Spring Harbor are on the third floor of the neuroscience center. They are cubicles, barely 2 feet by 3, draped in matte black cloth, the only illumination coming from dim red lights focused on simple mazes that flies learn to negotiate. The rooms are cloyingly warm and quiet but for the steady hiss of a humidifier. (''I spent five years in a room like that,'' Tully says as he gives me a tour. ''It explains a lot.'')

Tully's flies and Marcel Proust's famous narrator have more in common than one might think. The task performed in these little mazes and the reveries of ''Remembrance of Things Past'' both begin with the same thing: a sensory trigger. With a nod to Pavlov, Tully designed a memory test in which about 100 fruit flies are placed in a plastic chamber with wire mesh; researchers pipe in one of two distinctly different odors, octanol (which smells like licorice) or methylcyclohexanol (which Tully likens to the odor of ''tennis shoes in July''). At the same time, a dozen pulses of electric current pass through the mesh. With each pulse, the flies hop like a bunch of red-eyed commas.

During training, ''naive'' flies are exposed to one of the odors while receiving shocks. Then they are transferred, by a little ''elevator'' Tully designed, to what is called a T-maze; each arm of the T is scented with one of the two odors. After 10 training sessions, flies remember their lesson well and avoid the odor associated with the shocks, congregating in the other arm.

The key to creating long-lasting memory in fruit flies, it turns out, was the use of something called ''spaced training,'' which may have relevance to boomers who think their memories are fading. The phenomenon has been known for at least a century. In 1885, a German psychologist named Hermann Ebbinghaus, using himself as sole subject, discovered that he could memorize a list of nonsense syllables much better if he spaced out the learning sessions with a rest interval rather than simply repeating the drill over and over without a break.

Mindful of Ebbinghaus's conclusion, Tully began to space out the flies' training sessions with 15-minute rest intervals. Simple change, enormous ramifications. After about 10 training sessions, the flies developed robust long-term memories that lasted at least a week -- a significant period for an animal with a life span of 40 to 80 days. This gave Tully's colleague Jerry Yin, the molecular biologist of the team, a chance to see if CREB had anything to do with the formation of these long-term memories.

It did. In October 1994, the Cold Spring Harbor group showed that repressing CREB in flies prevented them from forming long-term memory. Another colleague, Alcino Silva, showed that in mice deprived of the CREB gene by genetic engineering, long-term memory was also blocked, although normal learning and short-term memory took place. So CREB now appeared to be important to long-term memory in three different animals.

CREB is an unusual and complicated gene, with, as Yin says, ''lots of bells and whistles -- very Baroque.'' In fruit flies, the CREB gene produces two different proteins, one an activator and the other a repressor, a yin and a yang that tend to cancel each other out. But the yang (the activator) seems to hang around a little longer in nerve cells than the yin (the repressor), and so with each repetition of an experience -- this is where spaced training in flies comes in, and perhaps rehearsals for Gershwin musicals -- the activator builds up. Once a certain threshold is crossed, CREB interacts with a neuron's DNA and turns on dozens of genes that convert what has been learned into long-term memory formation.

The next experiment was obvious -- and, truth be told, sexier. What would happen if somebody genetically rigged an animal to have a huge excess of the activator? The Cold Spring Harbor group did some extremely clever genetic engineering to accomplish this in fruit flies, and when Tully and his group returned to the cramped little fly rooms to test these particular flies, they made a stunning observation: the flies memorized the task after only one training session. By manipulating a single gene, the scientists had created photographic memory in an animal. Other researchers began to call it, with admiring envy, the ''smart fly.''

Tully likes to convey the power of CREB by describing it as an overseer controlling the work crews that actually remodel synapses. ''The general contractor sits there and organizes this process,'' he says. ''And when the structure is built, the general contractor goes away and you have a new structure. The general contractor is CREB.''

This is, to be sure, a highly simplified rendition of some rather complicated cellular events. CREB is present, for example, in many other cells of the body besides neurons, and biologists like Yin believe it is a general mechanism that allows a cell to keep track of outside stimulation. It is therefore suspected of playing a role in hormone metabolism, drug addiction and circadian rhythms.

Mark F. Bear, a neuroscientist at Brown University, has written that the CREB system represents ''one of the most exciting developments in neurobiology over the past few years'' because it seems to operate in a number of different animals. Soon after the creation of the ''smart fly'' three years ago, Kandel's group achieved the same photographic memory effect in Aplysia cells. Meanwhile, John Guzowski and James McGaugh of U.C. Irvine recently drizzled a drug that blocks CREB into the single region of a rat's brain that processes spatial information -- and the animal lost the ability to form a specific spatial memory. And just last March, Kandel's lab showed that mice that were genetically engineered to lack a single component in the pathway leading to CREB failed to form long-term memory.

If there has been a persistent message to emerge from biology in the last few years, it is that if you find a gene in nematodes or fruit flies or mice, the odds are very good that you'll find a similar gene in humans, often with the same function. Humans possess the CREB gene as well as a closely related gene called CREM, and both form part of the same pathway explored in Aplysia and fruit flies. As one fruit fly geneticist has put it, ''We're all working on the same genes -- we just don't know it yet.''

That is why research on and around the CREB switch -- both the upstream signals and the downstream genes -- has become a matter of both academic and commercial urgency. As Kandel knows, there are no guarantees and lots of surprises in the drug-discovery business. ''The reason you're hearing so much enthusiasm for CREB,'' he says, ''is that it hasn't been tested yet!'' While agreeing that the molecular genetics of memory clearly represents the wave of the future, McGaugh cautions that ''at the present time there is no way to turn genes on or off in a particular part of the brain at a particular time, so it's still a very blunt tool.''

Tully is more optimistic. A few weeks ago, he stood proudly before what he calls the ''Robotrainer'' -- a fully automated, computer-controlled and nearly operational wall of 48 identical plastic T-mazes designed to test memory, and memory-enhancing drugs, in fruit flies. ''Sort of the Henry Ford approach to memory research,'' he says. ''There are 23 genes already known to affect performance in this area, but we know there are about 100 genes involved in long-term memory. So our task now is to get all these genes on the table. Because trying to assemble a 100-piece jigsaw puzzle with only 23 pieces on the table is nuts.''

as is clear from the memory-suppressing ''neuralizer'' in the film ''Men in Black,'' Hollywood is still way ahead of the drug industry in developing ways to alter memory. The demand is there -- witness the thriving mail-order business for gingko biloba, piracetam and various other ''smart drugs'' of uncertain efficacy. But cooler heads point out that it will take years to develop dependable memory enhancers, whether based on CREB or other biological approaches, and that the F.D.A. has yet to be convinced that we even need a drug for age-related memory deficits.

The new Alzheimer's drugs, for example, reflect biological leads that were hot 10 and 15 years ago. Tacrine (brand name Cognex), approved for use in 1993 as the first Alzheimer's drug, was discovered in 1977; donepezil (brand name Aricept), approved in 1996, was developed in Japan in the early 1980's.

To hear researchers and doctors talk, first-generation drugs like Cognex and Aricept offer only limited relief, and may often be more effective at assuaging the guilt of family members than treating the Alzheimer's patient. ''They are the only drugs ever shown to do anything positive for patients with Alzheimer's disease,'' says Richard C. Mohs of Mt. Sinai School of Medicine. ''But they don't work for everybody, and the benefits are not dramatic and don't last forever.''

In addition to several second-generation derivatives of the tacrine approach currently awaiting F.D.A. consideration, a new generation of memory enhancers and suppressors is inching toward the clinic. Ten years ago, Gary Lynch, a neurobiologist at U.C. Irvine, showed that the AMPA receptor, a common synaptic connection between brain cells, played a role in learning and memory. He helped start a company called Cortex Pharmaceuticals to develop a class of drugs called Ampakines, which amplify the signals received by AMPA receptors and thus might function as memory enhancers. Doctors at the National Institute of Neurological Disorders and Stroke recently began testing a Cortex compound for memory loss in patients with mild to moderate Alzheimer's. A second study, conducted by the National Institute of Mental Health, is testing the drug for schizophrenia.

Enthusiasm about Ampakines can be hard to come by. ''There's been a lot of hype, but I don't know if their drug is any better than caffeine,'' says Charles F. Stevens, a neuroscientist at the Salk Institute for Biological Studies in San Diego. ''One way to find out would be to test your drug against caffeine and see if it worked better. But what if it didn't?''

Vincent F. Simmon, the president of Cortex, is well aware of such criticism; in addition to pointing out that Ampakines work in a biologically different way than caffeine, the company has even used the slogan ''Not just another cup of coffee!'' in its promotional materials.

The notion of a memory suppressant is about to be tested, too. Larry Cahill, a neurobiologist at U.C. Irvine, hopes to begin a clinical trial this year using Inderal, a well-established beta blocker given to cardiac patients, in a radically different setting. The rationale is that emotion is a strong component in memory formation, and that people who suffer traumatic experiences develop especially overwhelming memories of unpleasant events; the ''fight or flight'' rush of adrenaline helps cement especially durable, almost obsessive ''hyper'' memories. Beta blockers counteract the effects of adrenaline, and Cahill wants to treat about 30 to 40 victims of sexual assault to see if the drug, administered immediately after the event, can dampen the strength of these painful memories.

Although more powerful forms of memory-suppressing drugs have yet to be discovered, they already have a street name: Bleach. That's the name coined by an N.Y.U. film student who wrote a screenplay based on the CREB switch, and Tully doesn't think the idea is farfetched at all. ''The example I like to give,'' he says, ''are the little kids blown up in Oklahoma City. It's a traumatic event. A number of them already suffer recurrent nightmares. If you simply block the emotional memory of that event when they're in the hospital that first night, you have a therapy for subsequent psychological problems. I honestly believe that's a legitimate therapy.''

The Bleach scenarios are clearly more speculative, but also more troubling. What if Bleach is used by a dentist groping for more than rear molars, by a doctor palpating in places he oughtn't, by espionage experts, who would realize that operatives could not possibly spill secrets they were medicinally manipulated to forget? ''When you extrapolate that notion to the scenario where anyone inflicting any form of psychological or physical abuse on someone can block that person's memory of it,'' Tully says, ''you've got a problem.''

The possibilities are limited only by one's imagination. I began to picture a new generation of recreational esthetes, post-modern Prousts popping a pill and replaying in excruciatingly self-absorbed detail every aspect of an otherwise unremarkable day. (Makes you wonder if Nicholson Baker has already participated in a secret clinical trial.) Or consider the 21st-century day-tripper who wants to use a memory enhancer the way hippies used to drop LSD, to gild the lily of special events -- first or last days at college, the birth of a child, seeing the Rolling Stones on their Wheelchair Tour. Who needs a camera for a Kodak moment when you have pharmaceutically moved the developing room inside your head?

I even began to think about odd mnemonic side effects: some poor pre-med student is cramming for the M.C.A.T.'s late into the night, his brain revved on a memory enhancer, when a horde of mosquitoes begins to torment him; the image and sound burn into his memory, the hideous whine replayed again and again. Or you're in a car accident. Or you get hooked on ''Psycho'' while channel-surfing. Or happen to be prepping for a work presentation when the phone rings with bad news.

The drug companies have been careful to state that they are interested in cognitive enhancers only for well-defined medical conditions. But Cesare Mondadori, the head of research for central-nervous-system drugs at Hoechst Marion Roussel in Bridgewater, N.J., told me, ''Even though these compounds are aimed at treating the symptoms of patients, they have the potential of being used by 'normals.''' He reminded me that of all Prozac users -- who buy about $1.8 billion of the drug each year -- fully one-third have no medical need for it.

For his part, Tully sees ''Valley of the Dolls'' all over again. ''Do I think people are going to be bound by the ethical limits here?'' he asks. ''No.''

Not that everyone in the field thinks that memory drugs are inevitable. Mondadori has heard it all before -- the ''smart drugs'' of the 1970's, Ampakines in the 80's and now CREB. ''Memory is something that has a 200- to 300-million-year history of optimization and improvement,'' he says. ''If it were possible to improve it with a little bit of neurotransmitter or something, nature would have found it already.''

On Nov. 22, 1963, a Friday, I remember the buzz that swept through the hallways of my junior high school. That single cue -- word, number, year -- has become a common portal through which an entire generation, an entire society, pours on its way to personal memories as unique as a fingerprint.

All we heard at first was that Kennedy had been shot. I remember several cheerleaders, in their green-and-white Lancers outfits, bent over with emotion in the hallway, their faces contorted by sobs. (In one of those perverse cul-de-sacs of memory, I even remember thinking how odd this was: did they know him personally? The idea that 13-year-old girls could be so disfigured with sorrow seemed so. . .cheerleaderish, appropriating even the experience of grief as a privilege of the clique.) I remember most of all showing up in the administrative offices, as I did every day shortly before 3 P.M., to deliver messages over the public address system. The principal, a somber man named Glenn W. Bedell, intercepted me. (Why, I wonder now, have I wasted a few precious synaptic connections conjuring up his middle initial? And have I remembered it right?) Before I could even enter the booth, Mr. Bedell said, ''I'll handle the announcements today,'' and that's when I knew.

As I sit here, of sound mind and memory for at least a little longer, I find it difficult to imagine why normal people would need or want a memory pill to remember events as vivid as this. What we choose to remember -- and to forget, for that matter -- is intrinsic to who we are, all part of a unique fabric of temperament and fears and hopes. Tinkering with that process in a sense tinkers with the coherence of self.

Having a photographic memory may not be all it's cracked up to be, either. One day when I was talking to Tim Tully about the implications of an altered memory, I brought up what might be called the Sherashevsky Caveat. Tully nodded. He knew exactly where I was headed.

Sherashevsky was the human equivalent of one of Tully's fruit flies. He possessed a photographic memory. He could recite elaborate lists of nonsense words, complicated mathematical formulas, even stanzas of Dante in the original Italian after hearing them only once. At the request of A.R. Luria, the distinguished Russian psychologist who studied him in the 1920's, Sherashevsky flawlessly recited lists, words and poems he hadn't seen in 15 years.

Phenomenal memory comes at a price, however. Sherashevsky was a social and intellectual misfit. He tried dozens of jobs, failing as a journalist and musician and stockbroker before ultimately working as a music hall mnemonist, much like the ''Mr. Memory'' character in Hitchcock's ''Thirty-nine Steps.'' His memory worked by translating every sound and word into an elaborate image, and he became so enslaved to this separate visual reality that others perceived him as dull, awkward and absent-minded. Metaphors stumped him, poetry drove him crazy. Torn between the images presented by his memory and reality, he had no sense of the future.

As Luria later wrote, Sherashevsky ''lived in wait of something that he assumed was to come his way, and gave himself up to dreaming and 'seeing' far more than to functioning in life. The sense he had that something particularly fine was about to happen remained with him throughout his life -- something which would solve all his problems and make his life simple and clear. He 'saw' this and waited.. . .Thus, everything he did in life was merely 'temporary,' what he had to do until the expected would finally come to pass.''

My initial reaction to that passage was, Great, just what we baby boomers need -- a pill to increase our sense of expectation and entitlement. But Sherashevsky's message runs deeper than that. A drug that enhances memory might well have unexpected psychological side effects, tolerable in a patient with severe dementia but dangerous in normal people.

Early in ''Remembrance of Things Past,'' Proust likens memory to ''a rope let down from heaven to draw me up out of the abyss of not-being.. . .'' Giving ourselves too much memory might be a case of giving ourselves too much rope, the difference between memory that rescues and memory that imprisons.